Toad Prince Proteins and the Chemistry of Evolution

In the onset of diseases like Parkinson’s and Alzheimer’s, they’re the usual suspects. Inside cells, amyloid proteins have a tendency to amass like frogspawn and grab on to one another until their gluey corpus begins to block important pathways and cause vital processes to falter. While not everyone who possesses amyloid proteins suffers because of them—recent studies suggest they may have helpful roles in the body, as well—their sticky quality is dangerous, and as a result, amyloid proteins are generally perceived as personae non gratae by the bodies they’re part of.

However, according to a recent paper by ASA member David Andreu, professor of chemistry at Pompeu Fabra University in Barcelona, Spain, amyloids may be something like the toad princes of the protein world. Although they’re mostly seen as undesirable, amyloid proteins possess certain features in their amino acid structure (amino acids is what proteins are made of) that could potentially transform them into proteins with beneficial rather than hazardous properties.

All it would take is a wave of the evolutionary wand (over a few million years, that is).

David explains, “This tendency that some proteins have of sticking to each other is called ‘aggregation,’ and in general, it’s bad news. The proteins per se aren’t bad, but once they begin to stick to each other, it becomes harmful. This is for instance the case with the amyloid proteins causing Parkinson’s and Alzheimer’s diseases. When these proteins start to form aggregates, it triggers an alarm mechanism and cells try to get rid of them by a process called apoptosis. Apoptosis refers to programmed cell death, a normal part of the life and death cycle of cells in which cells commit what one could call ‘cellular suicide’ rather than go along with the aggregation taking place within them.”

While it’s better for cells to kill themselves upon recognition of the danger they pose when potentially harmful processes such as are taking place within them, David and his team propose a potential “win-win” situation in which cells experiencing protein aggregation might evolve to respond in a more positive way than jumping off the proverbial building.

As the workhorses inside every living cell, proteins perform the various tasks that make all living things functional. They’re made up of chains of amino acids arranged into singular shapes. “What we showed is that there are certain positions in the amino acid structure of amyloid proteins that are, so to say, privileged,” says David. “Privileged in the sense that if an adequate rate of mutation occurred over the course of evolution, some of these amino acids could potentially transform the protein’s three-dimensional structure into the alpha-helix shape characteristic of antimicrobial proteins (AMPs), one of the main players in innate immunity, the body’s first line of defense against infection. These changes would transform the amyloid protein from one that’s offensive to cells to one that’s defensive of the entire organism.”

If that sounds like the all-too-happy ending of a myth or fairy tale, for any skeptics out there, David also explained the finding via negativa, “If someone came along who didn’t believe in evolution or who was suspicious of these results, he or she might point out that in showing it’s chemically possible for an amyloid protein to become an AMP through evolutionary means, we’re introducing a lot of human intelligence into the process that doesn’t exist in nature. Any experiment we do in the 21st century can be done in a few months with the help of sophisticated machines and algorithms, so it’s not random and time-consuming like evolution in the wild. But what we’ve done is to show how this particular transformation would be a relatively uncomplicated process, and as every evolutionary biologist knows, it’s possible that this kind of thing can happen over many millions of years.”

While David’s lab primarily works on the protein chemistry of AMPs, not their evolution, the team’s hypothesis yielded such conclusive predictions that it was published in one of the world’s most prominent chemistry journals, Angewandte Chemie. “Mostly, our lab is interested in developing synthetic versions of antimicrobial proteins and peptides into biomedical tools. Our approach, when looking at a protein with AMP features, is to try and cut it down, trim the fat (so to speak), and make it into a useful machine with therapeutic potential,” says David. “The intuition for this experiment came to me and a postdoc of mine when we were both intrigued by recent reports mentioning that some amyloid proteins may have antimicrobial properties, and some AMPs have a tendency to aggregate. There seemed to be a cross-talk between the two groups. While scientists who deal with amyloids are obviously concerned about their aggregation, people like us are interested in what the AMPs are programmed to attack. Our intuition when the two sides came together showing each other’s properties was that—wow, perhaps these two groups are more related than we thought.”

Since there’s no physical record of how amyloids and AMPs evolved, David and his colleagues wondered which came first: Is one group the parent of the other? Did nature eventually ‘decide’ that it could develop new features in proteins and make something useful out of them?”

The evidence is that amyloid proteins are, in fact, older than AMPs, which appear to have developed later (i.e., they exist in more “highly evolved” organisms, whereas amyloids are more common throughout the biological world).

Andreu and his team chose 25 of the most abundant human amyloid proteins and, using bioinformatic algorithms, identified the regions more likely to be involved in aggregation. Then, using these regions as templates, they introduced certain types of mutations in particular places (in this case, increasing positive charge), which turned an inactive stretch of amino acids into an active antimicrobial site. As controls, the team also took random sequences of amino acids, as well as regions with low predicted scores of aggregation, and attempted to do the same, but found that only when they started with an amyloid protein did they end up with an AMP.

“It was really exciting,” says David, “You need the amyloid-prone sequence as a starting point. Applying the same strategy to a non-amyloid stretch doesn’t lead to antimicrobial properties. The referees at Angewandte Chemie were very demanding about negative controls, and the fact that such controls were so clearly negative was a strong support for our hypothesis that, over the course of years and years of evolution, it’s possible that some amyloid proteins might have evolved into AMPs and thus given their organisms an evolutionary advantage.

“Of course some people, particularly some creationist Christians, may take issue with this particular path of evolution we’re proposing,” David continues. “But it’s really quite unassuming. We’re just showing that there are fairly simple ways in which proteins can acquire new features…”

David pauses for a moment, perhaps weighing the significance of the slow and plodding, two-steps-forward-one-step-back universe that human research suggests against the thought of instantaneous, divinely compelled creation.

“As a scientist and a chemist, I am happier with the first option,” David then says. “As a Christian, I believe God is all-powerful—but I have no problem with the idea of the Creator working through evolutionary change. I don’t see any conflict in being a theist and at the same time believing that God used physical and chemical processes in creation. Rather than having God intervening at this or that step, I think God endowed His creation with robust mechanisms that can explain quite satisfactorily the universe and the amazing diversity of our world in particular. That there is a Creator underlying something so powerful as the genetic code and the intelligence behind it all—is absolutely wonderful.”

In addition to research in protein chemistry, David is also interested in faith-science questions. He was particularly motivated by the 2010 issue of Perspective on Science and Christian Faith, the academic journal of the ASA, dedicated to “The Search for the Historical Adam.” So provocative and controversial were the ideas explored in that issue that two contributors had to defend their faith to an investigative panel, and one ended up resigning his job teaching science at a Christian college. Concerned by the lack of awareness on these subjects among in the Spanish-speaking protestant community, David and Pablo de Felipe, a Madrid-based molecular biologist member of Christians in Science and the Faraday Institute, have taken up the task of extracting the controversial articles in PSCF and translating them into Spanish.

“We are doing this as a service to the Spanish readers so they, too, can enjoy, criticize, and start the same kinds of discussions they’re already having in the English-speaking world,” says David. “I have lived in the US for extended periods of time, and the science/faith debate is completely different to that in countries like Spain. In the US, people who don’t identify as Christians tend to give philosophical, theological, or scientific reasons for why they don’t believe in God. Here, it’s more historical and sociological than intellectual. We have the added historical dimension of a domineering Catholic church, which still casts a powerful shadow on many areas of our society and culture. So the Spanish (and to some extent the Latin American) scene is quite different from that of the US, the UK or other European countries. Here, faith-science issues interest a minority within a minority.

“Within this minority (i.e., the Spanish evangelicals), creationist viewpoints are practically unchallenged,” David continues. “The protestant denominations that grew up in the 20th century in Spain were largely the outcome of missionary work by Southern Baptist, Pentecostal, and other fundamentalist denominations, mostly from the US. Most of the missionaries who came were opposed to evolution, and this was the only position available in our churches as I and others in my generation were growing up. By God’s grace some of us have managed to challenge these views without losing our faith in the process, but many casualties have taken place along the line.

For years, they’ve been concerned about the situation, but David thinks they’ve probably been overcautious about not rocking the boat. “I think that now the time is ripe to bring these issues to the forefront,” says David. “In most seminaries training people for ministry in Spain, chances are that faculty will either refuse to give an opinion of theistic evolution, or, more likely, be openly critical of the idea. Many pastors are still convinced that evolution and faith don’t mix well, and that’s a pity, because it confines meaningful dialogue to very small circles. Eventually, though, they will realize they can’t ignore the issue any longer, because churches keep losing young people who go to college and can’t relate what they learn in science classes to what they were told in Sunday school.”

Although it’s tempting for scientifically minded Christians to wish all their brothers and sisters could simply understand and appreciate the challenging ideas science brings to their faith, the greater body of the Christian church isn’t going to evolve all at once. But perhaps those same places and congregations where science is currently most discouraged and understanding at its weakest are in some ways similar to the “privileged positions” David and his group studied in chains of amino acids. With the simple influence of patience, love, and respectful conversation with those who may have never heard from a sympathetic scientist before, the fundamentalist Christianity around the world could transform from a religion that’s at best suspicious of scientific knowledge to one that promotes and most ardently defends it.

Like the existence of life in the universe, such a reality appears highly unlikely, even unbelievable—but it’s certainly not impossible.

What will be available soon are not complete translations but fairly extensive extracts of the 3 papers. They are to appear in Aletheia, the theological journal of the Spanish Evangelical Alliance. Unfortunately the journal is only available on paper for now. We’re trying to convince them to have the three extracts put up on their website but I can’t guarantee they will do that. For more info, check http://www.aeesp.net/html/publicaciones/publicaciones.php